Distribution of Alcohol in the Body
The equilibrium concentration of alcohol in a tissue depends on the relative water content of that tissue. Equilibration of alcohol within a tissue depends on the water content, rate of blood flow and the tissue mass Ethanol is practically insoluble in fats and oils, although like water, it can pass through biological membranes. Ethanol distributes from the blood into all tissues and fluids in proportion to their relative content of water. The concentration of ethanol in a tissue is dependent on the relative water content of the tissue, and reaches equilibrium quickly with the concentration of ethanol in the plasma. There is no plasma protein binding of alcohol.
The same dose of alcohol per unit of body weight can produce very different blood alcohol concentrations in different individuals because of the large variations in proportions of fat and water in their bodies, and the low lipid: water partition coefficient of ethanol. Women generally have a smaller volume of distribution for alcohol than men because of their higher percentage of body fat. Women will have higher peak blood alcohol levels than men when given the same dose of alcohol as g per kg body weight but no differences occur when given the same dose per liter of body water. First pass metabolism of alcohol by the stomach, which may be greater in males, may also contribute to the higher blood alcohol levels found in women.
The breath analyzer test for estimating blood alcohol concentrations is dependent on the diffusion of ethanol from pulmonary arterial blood into the alveolar air. The ethanol vapor in breath is in equilibrium with the ethanol dissolved in the water of the blood at a blood : breath partition coefficient of about 2100:1. An excellent recent review which summarizes many of these pharmacokinetic interactions can be found in.
Factors Affecting Alcohol Absorption
LIST 2 describes some factors which affect the absorption of alcohol. Absorption of alcohol from the duodenum and jejunum is more rapid than from the stomach, hence the rate of gastric emptying is an important determinant of the rate of absorption of orally administered alcohol.
- Alcohol crosses biological membranes by passive diffusion, down its concentration gradient. Therefore, the higher the concentration of alcohol, the greater is the resulting concentration gradient, and the more rapid is the absorption.
- Rapid removal of alcohol from the site of absorption by an efficient blood flow will help maintain the concentration gradient and thereby promote absorption.
- Alcohol has irritant properties and high concentrations can cause superficial erosions, hemorrhages and paralysis of the stomach smooth muscle. This will decrease alcohol absorption,
- Peak blood alcohol levels are higher if ethanol is ingested as a single dose rather than several smaller doses, probably because alcohol concentration gradient will be higher in the former case.
- In general, there is little difference in the rate of absorption of the same dose of alcohol administered in the form of different alcoholic beverage i.e., blood ethanol concentration is not significantly influenced by the type of alcoholic beverage consumed.
- The presence of food in the stomach retards gastric emptying and thus will reduce the absorption of alcohol, the “don't drink on an empty stomach” concept. Meals high in either fat, or carbohydrate or protein are equally effective in retarding gastric emptying. The major factor governing the absorption rate of alcohol is whether the drink is taken on an empty stomach or together with or after a meal.
The blood alcohol concentration is determined by the amount of alcohol consumed, by the presence or absence of food in the stomach, factors which affect gastric emptying and the rate of alcohol oxidation.
First Pass Metabolism of Alcohol in the Stomach
Some of the alcohol which is ingested orally does not enter the systemic circulation but may be oxidized in the stomach by ADH isoforms such as σADH and class I and class III ADH. This first pass metabolism could modulate alcohol toxicity since its efficiency determines the bioavailability of alcohol. Ethanol is rapidly passed into the duodenum from the stomach in the fasted state. This will minimize first pass metabolism and thereby play a role in the higher blood alcohol concentrations observed in the fasted versus the fed state.
First pass metabolism has been reported to be low in alcoholics, especially in alcoholic women because of decreased ADH activity. This may be important in the increased sensitivity to alcohol and the higher blood alcohol concentrations in women than in men after an equivalent oral dose of ethanol. Several drugs, including H2 receptor blockers such as cimetidine or ranitidine, or aspirin inhibit stomach ADH activity. This will decrease first pass metabolism by the stomach, and hence, increase blood alcohol concentrations.
The overall significance of first pass metabolism by the stomach is controversial. The speed of gastric emptying modulates gastric and hepatic first pass metabolism of alcohol. Considering the greater levels of alcohol metabolizing enzymes in the liver compared to the stomach, it seems likely that liver plays the major role in alcohol metabolism.
Alcohol Metabolism-General Principles
LIST 3 describes some general principles of alcohol metabolism.
The major enzyme system(s) responsible for the oxidation of ethanol, alcohol dehydrogenase, and to a lesser extent, the cytochrome P450-dependent ethanol-oxidizing system, are present to the largest extent in the liver. Liver damage lowers the rate of alcohol oxidation and hence, elimination from the body. Ethanol is a nutrient and has caloric value (about 7 kcal per gram; carbohydrates and protein produce 4 kcal per gram, while fat produces 9 kcal). However, unlike carbohydrates (glycogen in liver and muscle) and fat (triglycerides in adipose tissues and liver) which can be stored and utilized in time of need e.g. fasting, alcohol is not stored and remains in body water until eliminated. Whereas metabolism of the major nutrients is under hormonal control, e.g insulin/glucagon, leptin, catecholamine, thyroid hormones, generally, there is little hormonal regulation to pace the rate of alcohol elimination. In view of these considerations, there is a major burden on the liver to oxidize alcohol in order to remove this agent from the body.
Animals with small body weight metabolize alcohol at faster rates than larger animals e.g. the rate of alcohol elimination in mice is 5 times greater than the rate in humans. These rates of alcohol metabolism correlate with the basal metabolic rate for that species, indicating that the capacity to oxidize ethanol parallels the capacity to oxidize the typical nutrients. However, it is important to note that alcohol-derived calories are produced at the expense of the metabolism of normal nutrients since alcohol will be oxidized preferentially over other nutrients.
